Tumor angiogenesis is an attractive target for cancer therapy and chemoprevention. The recent proven efficacy of various anti-angiogenic therapies in recent clinical trials underscore the potential of this approach. Components of intracellular signaling pathways that regulate endothelial cell survival may provide particularly attractive molecular targets for development of such strategies, especially those pathways that regulate endothelial cell apoptosis. During angiogenesis, in order to migrate, endothelial cells must break both cell-cell and cell-extracellular matrix attachments, a process that is inherently pro-apoptotic. Our recent work demonstrates that the ras/Erk pathway nuclear effectors, Ets1 and Ets2, play a critical role in endothelial cell survival and migration during development that is specific for this cell type. The studies proposed here will define biological and molecular mechanisms by which Ets1 and Ets2 act in normal endothelial cells, and will determine whether these genes also affect tumor endothelial cell function within the tumor microenvironment. Understanding how signaling pathways involved in complicated biological processes like angiogenesis function beyond cell membranes, and the likely critical role of the extracellular matrix in this communication, is one of the leading challenges for the microenvironment field over the next 5 years. The ras/Ets pathway may provide a paradigm for studying signaling beyond cell membrane in the tumor microenvironment. Tumor angiogenesis is an attractive target for tumor therapy. This project will potentially identify new molecular targets that will be useful for triggering cell death in tumor endothelial cells, affecting tumor growth and metastasis.